Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New 2-[2'-(dimethylamino)ethyl]-3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at the 6- and 7-positions were prepared. Nucleophilic aromatic displacement was a key reaction in the syntheses. Ten of the new compounds were more potent than the unsubstituted compound, azonafide, in a panel of tumor cells including human melanoma and ovarian cancer and murine sensitive and MDR L1210 leukemia. They also were less cardiotoxic in cell culture. Four of these compounds were not cross-resistant with the MDR leukemia, and one of them, 6-ethoxyazonafide, was nearly as potent against solid tumor cells as leukemia cells. These compounds also had good potency against human breast, colon, and lung cancer cells, including doxorubicin and mitoxantrone resistant cell lines. Advantages of the new analogues over azonafide were less in vivo, but 6-ethoxyazonafide was more effective against L1210 leukemia and subcutaneous B16 melanoma in mice. Although correlations of antitumor potency in cells and physicochemical properties of substituents were not found, there were statistically significant correlations of DNA melt transition temperature (delta Tm) with potency in solid tumor cells and sensitive and MDR resistant L1210 leukemia cells for 6-substituted azonafides and with solid tumors for 7-substituted azonafides.
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PMID:6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-diones: synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships. 864

Seventy-eight patients: 45 children, 33 adults and 27 normal healthy donors were enrolled in the study. Expression of P-glycoprotein (P-gp) was evaluated with three monoclonal antibodies (MAb's) directed to intra-(C219, JSB-1) and extra-cellular (MRK-16) epitopes of P-gp and immunocytochemical (IC) APAAP staining method. Twenty-seven healthy donors peripheral blood mononuclear cells (PBMC) were investigated by means of IC and FACScan analysis. Positive staining for P-gp was detected in 31% children's and 33% adults' leukemia samples. No reactivity of three MAb's was observed with peripheral blood mononuclear cells (PBMC) by means of IC. Flow cytometry analysis with C219 MAb revealed staining for P-gp present on sub-population of lymphocytes and monocytes. P-gp (+) as well as P-gp (-) cases were compared in respect to clinical outcome, FAB classification and blood group. Complete remission (CR) was achieved in 12/14 (85%) children's and 9/11 (81%) adults' P-gp (+) leukemia cases. Within the P-gp (-) leukemia cases CR was observed in 24/29 (82%) and 18/22 (81%), respectively. Partial remission, relapse, resistance and death were noticed in 14% children's and 18% adults' P-gp (+) samples. In P-gp (-) cases these parameters were observed in 17% and 18%, respectively. These results raise the question whether the expression of P-gp can be used as single prognostic marker to detect multidrug resistance (MDR phenomenon) in vivo?
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PMID:Is P-glycoprotein a sufficient marker for multidrug resistance in vivo? Immunohistochemical staining for P-glycoprotein in children and adult leukemia: correlation with clinical outcome. 875 Jun 36

Thirty-six French centres are involved in an evaluation of the techniques used for MDR phenotype measurement. Until now, 14 samples of various kinds of leukemia (mainly acute myelogenous leukemia) and three cell lines with different levels of resistance were sent by one centre and tested. MRK16 antibody was used for flow cytometry and immunocytochemistry, RNA was measured by RT-PCR, rhodamine or anthracyclin efflux were tested for functional assay. Wide discrepancies were observed in the results, mainly with flow cytometry, specially for the samples with a probable low level of MDR1 expression. The importance of histogram interpretation was documented by the comparative analysis of results obtained on cells already marked with MRK16, fixed and sent to all centers. The use of the ratio of the mean of fluorescence, instead of percentage, should help for standardization. The use of only one control RNA (used at different dilutions) for standardisation of RT-PCR could help in decreasing the discrepancies observed. The mean of fluorescence should also be used for expressing the rhodamine cell content.
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PMID:[Multicentric evaluation of MDR phenotype in leukemia: intermediate analysis of the French study]. 886 43

Retroviral transfer of the multidrug-resistance 1 (mdr1) cDNA into primary human hematopoietic progenitor cells (HPC) of cancer patients undergoing high-dose chemotherapy has been proposed to protect the bone marrow from the dose-limiting cytotoxicity of cytostatic agents. Preclinical studies performed with vectors derived from the Moloney murine leukemia virus (MoMuLV) or the related Harvey murine sarcoma virus have established that chemoprotection of HPC is feasible. The efficacy of vector-mediated multidrug-resistance under high doses of cytostatic agents, however, remained unclear. We report here that this goal can only be achieved with improved vector design. Novel vectors termed SF-MDR and MP-MDR, which are based on the spleen focus-forming virus or the myeloproliferative sarcoma virus for the enhancer and the murine embryonic stem cell virus for the leader, significantly elevate survival of transduced primary human HPC under moderate doses of colchicine and paclitaxel in vitro when compared with a conventional MoMuLV-based vector. Importantly, SF-MDR and also MP-MDR confer an absolute advantage at high doses of paclitaxel in vitro corresponding to peak plasma levels achieved in patients during chemotherapy. This observation has important consequences for a variety of ongoing and planned gene therapy trials.
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PMID:High-dose multidrug resistance in primary human hematopoietic progenitor cells transduced with optimized retroviral vectors. 889 5

New 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3- diones with substituents at the 4, 8, 9, 10, and 11 positions were synthesized. Diazonium salts prepared from aminoazonafides were key intermediates for many of the analogues. Six of the new compounds were more potent than azonafide in a panel of tumor cells including human melanoma and ovarian carcinoma and murine L1210 leukemias. Three of these compounds, the 10-OCH3, 10-OC2H5, and 10-F analogues, had better ratios of cardiotoxicity to tumor-cell toxicity than azonafide. Eight compounds were not cross-resistant with MDR L1210 leukemia, and the 10-CN analogue was more potent against solid tumor cells than leukemia cells. The 9-OH, 10-CN, and 10-F analogues had high potency against both sensitive and resistant cell lines of MFX 7 breast carcinoma and WiDr colon carcinoma and sensitivity A599 lung carcinoma. Advantages of the 10-Cl, 10-NH2, and 10-CN analogues over azonafide were apparent in P388 leukemia in mice, and the 10-CN analogue was more effective than doxorubicin in this assay. Quantitative structure-activity relationship studies revealed statistically significant correlations between DNA binding strength of 8- and 10-substituted azonafides, as measured by deltaTm, and toxicity to tumor cells. There also were correlations between substituent size, as measured by MR, and cytotoxicity for 9- and 10-substituted azonafides and between MR and deltaTm for 4- and 11-substituted azonafides. Lipophilicity of substituents (pi) correlated with cytotoxicity for 9-, 10-, and 11-substituted azonafides. These results lend support to a model in which DNA binding strength influences cytotoxic potency, and lipophilicity increases DNA binding whereas large substituents decrease it.
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PMID:2-[2'-(Dimethylamino)ethyl]-1,2-dihydro- 3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at positions 4, 8, 9, 10, and 11. Synthesis, antitumor activity, and quantitative structure-activity relationships. 896 May 58

Circulating hematopoietic progenitor cells include pluripotent stem cells expressing indefinite self-renewal capacity and, therefore, can be used for restoring hematopoiesis following myeloablative treatment. A transient shifting of progenitor cells from extravascular sites into the circulation by chemopriming and/or cytokine treatment enables the collection by apheresis of a sufficient number of progenitor cells to guarantee engraftment. The addition of new cytokines (e.g., thrombopoietin) and large volume apheresis will increase peripheral blood progenitor cell (PBPC) procurement efficiency, whereas the risk of concurrently mobilizing clonogenic tumor cells in patients with solid tumors and hematologic malignancies remains to be carefully evaluated. As compared with bone marrow (BM) progenitor cells, the use of PBPCs significantly shortens the recovery of WBC and platelets following transplantation. Most recently, successful allogeneic transplantation of PBPCs has been reported without increasing the incidence and severity of acute graft-versus-host-disease. Due to the more than one log higher number of lymphoid subsets contained in a PBPC allograft, one might expect a more pronounced graft-versus-leukemia effect in the transplant patient. Similar to BM cells, ex vivo manipulation of mobilized apheresis products is used or being developed (ultralight density percoll gradient, CD8 depletion, selection of graft facilitating cells, CD34+ cell purification and others). The transduction and long-term expression of marker genes and, most recently, therapeutic genes (e.g., MDR-1) in PBPCs have been successfully demonstrated by several groups in patients with hematologic malignancies and selected solid tumors. It is expected that, based on the easier procurement of hematopoietic stem cells and advantageous engraftment characteristics, PBPCs in both autologous and allogeneic transplant situations will eventually replace BM-derived progenitor cells.
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PMID:Peripheral blood progenitor cell transplantation: a replacement for marrow auto- or allografts. 899 38

A novel resistant variant of murine P388 leukaemia, P388/SPR, was identified by de novo resistance to doxorubicin (DOX) in vivo. This mutant displayed a similar level of cross-resistance to etoposide (VP-16) and other topoisomerase II (topo II) inhibitors. Further analysis of the phenotype revealed a broad cross-resistance to vinca alkaloids, alkylating agents, antimetabolites, aphidicolin and UV light. Low-level expression of mdr1 and P-glycoprotein (P-gp), as well as a modest impairment of cellular drug accumulation and partial reversion of resistance to DOX and VP-16 by cyclosporine, confirmed a moderate role of P-gp in conferring drug resistance in P388/SPR cells. Consistent changes in neither topo II expression or activity nor glutathione metabolism could be detected. Induction of apoptosis was significantly reduced in P388/SPR cells, as indicated by minimal DNA fragmentation. Analysis of oncogenes regulating apoptotic cell death revealed a marked decrease of bcl-2 in combination with a moderate reduction of bax protein, but a striking overexpression of the long form of the bcl-X protein. Transfection of human bcl-X-L into P388 cells conferred drug resistance similar to that of P388/SPR cells. The data suggest that overexpression of bcl-X-L results in an unusual phenotype with broad cross-resistance to non-MDR-related cytotoxins in vitro, and provide an interesting example of spontaneous overexpression of another member of the bcl-2 gene family in cancer.
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PMID:Spontaneous overexpression of the long form of the Bcl-X protein in a highly resistant P388 leukaemia. 901 37

We compared bcl-2 with P-glycoprotein expression (C494 and JSB1), and both with ex vivo chemosensitivity by Differential Staining Cytotoxicity (DiSC) assay (25 cytotoxic drugs), in 76 fresh haematological specimens, including 51 chronic lymphocytic leukaemias (CLL). Strong correlations were seen between bcl-2 and Pgp expression in both CLL (r = 0.5; p < 0.001) and AML (r = 0.9; p < 0.001) although bcl-2 expression was only raised in Pgp positive cells. However, there was no correlation between high or low marker levels and either ex vivo drug sensitivity (-0.30 < r < 0.37; p all > 0.1) or patient survival (chi 2 < or = 0.1; p > 0.7). One B-CLL, one PLL and one hairy cell leukaemia were negative for both bcl-2 and Pgp, whilst 3 T-cell specimens were bcl-2 negative but strongly positive for Pgp. These results suggest that the expression of Pgp and bcl-2 may be interlinked and related to immunophenotype and that clinical sensitivity to MDR-inducing and/or apoptosis-inducing drugs is best determined by ex vivo chemosensitivity testing rather than measurement of Pgp or bcl-2 expression.
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PMID:Correlation of bcl-2 with P-glycoprotein expression in chronic lymphocytic leukaemia and other haematological neoplasms but of neither marker with ex vivo chemosensitivity or patient survival. 904 70

Drug resistance, a major obstacle to cancer chemotherapy, can be mediated by MDR-1/P-glycoprotein. Deletion of the first 68 residues of MDR-1 in an adriamycin-selected cell line after a 4;7 translocation, t(4q;7q), resulted in a hybrid mRNA containing sequences from both MDR-1 and a novel chromosome 4 gene. Further selection resulted in amplification of a hybrid gene. Expression of the hybrid mRNA was controlled by the chromosome 4 gene, providing a model for overexpression of MDR-1. Additional hybrid mRNAs in other drug-selected cell lines and in patients with refractory leukemia, with MDR-1 juxtaposed 3' to an active gene, establishes random chromosomal rearrangements with overexpression of hybrid MDR-1 mRNAs as a mechanism of acquired drug resistance.
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PMID:Gene rearrangement: a novel mechanism for MDR-1 gene activation. 910 39

Chemotherapy for adult T-cell leukemia (ATL) has been reported to fail to induce complete remission because of drug resistance in most patients. We have examined the expression of an ATL-derived factor (ADF)/thioredoxin in relation to resistance to adriamycin (ADM) in various T-cell leukemia cell lines including ATL cell lines. Immunoblot analysis demonstrated that ATL cell lines expressed ADF/thioredoxin at levels 2.8 to 12 times those of other T-cell acute lymphocytic leukemia (T-ALL) cell lines, and that ATL cell lines were 2 to 15 times more resistant to ADM than other T-ALL cell lines. Therefore, we established ADM-resistant cell lines from three different ATL cell lines, and examined the correlation between ADM resistance and expression of ADF/thioredoxin. ADM-resistant ATL cell lines were also found to be resistant to other drugs such as cisplatin and etoposide, and they expressed ADF/thioredoxin at levels 5 to 10 times those of parent ATL cell lines. Diamide and sodium selenite, which have been reported to inhibit ADF/thioredoxin, restored the sensitivity to ADM in ATL and ADM-resistant ATL cell lines. The MDR-1 gene product, a membrane P-glycoprotein (Pgp), was not expressed on ATL cell lines or ADM-resistant ATL cell lines. Topoisomerase II and glutathione peroxidase activities in T-cell leukemia cell lines were not correlated with ADM resistance. These results suggest that ADF/thioredoxin may play an important role in the drug resistance of ATL cells to ADM.
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PMID:Possible roles of an adult T-cell leukemia (ATL)-derived factor/thioredoxin in the drug resistance of ATL to adriamycin. 911 92


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